Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.CO[CH:13](OC)[N:14](C)C.O.Cl.NO>CO>[CH:1]1([C:4]2[O:10][N:14]=[CH:13][C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: NO
Solvent: O
Solvent: CO
Product: O=C(O)c1cnoc1C1CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Methyl 3-cyclopropyl-3-oxopropanoate (0.28 g, 2 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.24 g, 2 mmol) was mixed and heated for 20 h at 60° C. The bright yellow oil was dissolved in methanol (2 mL) and H2O (1 mL) and hydroxylamine hydrochloride (0.14 g, 2 mmol) was added, resulting in a pH of ca 5. The reaction was heated for 90 min at 60° C. The solvents were evaporated and the residue refluxed in acetic acid: conc. HCl (3+3 mL) for 4 h. The mixture was stored at room temperature for 2 days and the solid was filtered off and dried in vacuum to yield the title compound as a grey solid. This compound is also commercially available. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.18-1.28 (m, 2 H) 1.28-1.35 (m, 2 H) 2.78-2.90 (m, 1 H) 8.45 (s, 1 H)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10](Br)[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2].[CH2:13]([Zn]CC)[CH3:14]>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:13][CH3:14])[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2]
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1
Reactant: CC[Zn]CC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCc1cc(C=O)cc(C(=O)O)c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Under nitrogen, Pd(dppf) (97 mg, 0.119 mmol) was added to a stirred solution of 3-formyl-5-bromo-benzoic acid (3.00 g, 11.92 mmol) in dioxane (100 mL). Diethyl zinc (14.7 g, 17.9 mmol, as a 15% solution in toluene) was added and the mixture was stirred at 75° C. for 1 h. The reaction was quenched by adding water (5 mL) and the solvent was evaporated to a volume of about 50 mL. The mixture was basified by adding sat. aq. ammonia (1 mL). The mixture was filtered and the filtrate was acidified by adding formic acid (4 mL) before it was separated by prep. HPLC to give the title compound as a colourless resin (1.17 g). LC-MS*: tR=0.44 min, [M−H]−=177.26; 1H NMR (D6-DMSO): δ 1.24 (t, J=7.8 Hz, 3H), 2.77 (q, J=7.5 Hz, 2H), 7.92 (t, J=1.8 Hz), 8.08 (t, J=1.8 Hz, 1H), 8.26 (t, J=1.5 Hz, 1H), 10.06 (s, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32](OC)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=2)(=[O:38])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1.O>CCOCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32]([C:2]5[S:3][CH:4]=[CH:5][N:6]=5)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:46])[F:47])[CH:40]=2)(=[O:38])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1
Reactant: Brc1nccs1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cccc(C(F)(F)F)c1)C2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cccc(C(F)(F)F)c1)C2
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 57.8 %

Procedure:
2-Bromothiazole (187 mg, 1.139 mmol) in dry ether (2 mL) was added to butyllithium (1.6M in hexanes) (729 μl, 1.167 mmol) in dry ether (4 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes. A solution of (R)-methyl 1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (200 mg, 0.373 mmol) in dry ether (4 mL) was added dropwise and the reaction mixture was stirred for 30 minutes at −78° C. Water (20 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried (magnesium sulfate), and solvent removed to give a yellow oil. The crude product was purified first by chromatography on silica gel (gradient: 0 to 40% isohexane in ethyl acetate) followed by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 40-65% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (127 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.73 min, m+H=589.0; 1H NMR (400 MHz, CDCl3): δ 8.04 (1H, d, J=3.1 Hz), 7.97 (1H, s), 7.90 (1H, d, J=7.9 Hz), 7.81 (1H, d, J=7.9 Hz), 7.70-7.59 (2H, m), 7.46-7.39 (2H, m), 7.30 (1H, s), 7.13-7.19 (2H, m), 6.53 (1H, d, J=2.2 Hz), 5.54 (1H, dd, J=12.4, 2.0 Hz), 4.21 (1H, d, J=16.8 Hz), 3.93-3.89 (1H, m), 2.95-2.84 (2H, m), 2.80 (1H, d, J=12.5 Hz), 2.61-2.52 (2H, m).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16](O)=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:40][O:41][NH:42][CH3:43]>C(Cl)Cl.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16]([N:42]([O:41][CH3:40])[CH3:43])=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(-c2nc(C(=O)O)c(-c3ccccc3Cl)o2)c(C)cn1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1nc(-c2cc(NC(C)=O)ncc2C)oc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-1,3-oxazole-4-carboxylic acid (0.303 g, 0.815 mmol) in DCM (2 mL) was added CDI (0.14 g, 0.87 mmol). The reaction mixture was allowed to stir at rt for 30 min, then at reflux for 30 min. The reaction mixture was allowed to cool to rt and TEA (0.125 mL, 0.896 mmol) and N-methoxymethanamine hydrochloride (0.835 g. 0.856 mmol) were added. The reaction mixture was allowed to stir at rt overnight and then diluted with water. The aqueous solution was separated and extracted with DCM. The organic solutions were combined, washed sequentially with 10% citric acid, saturated aq. NaHCO3 (50 mL) and brine, dried over Na2SO4, filtered and concentrated to give 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-N-methoxy-N-methyl-1,3-oxazole-4-carboxamide (0.187 g, 55%), which was used without purification in the next step. LCMS (FA): m/z=415.4 (M+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[Na+].O>C(O)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:13][C:14](=[O:15])[CH:16]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:1])([F:11])[F:12]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1C(F)(F)F)C=Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
2-(Trifluoromethyl)-benzaldehyde (1w, 0.75 ml, 5.7 mmol) and acetone (19, 0.21 ml, 2.8 mmol) were combined in ethanol (20 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.34 g, 8.5 mmol) and water (15 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to afford 0.92 g (87%) of a yellow solid: mp 131-133° C. [expected mp 131° C.]; 1H NMR: δ 6.99 (d, 2H, J=15.9 Hz), 7.48 (t, 2H, J=7.6 Hz), 7.56 (t, 2H, J=7.0 Hz), 7.70 (d, 2H, J=7.7 Hz), 7.77 (d, 2H, J=7.6 Hz), 8.07 (d, 2H, J=15.7 Hz); 13C NMR: δ 123.9, 126.2, 127.9, 128.8, 129.4, 129.7, 132.1, 133.7, 139.1, 188.0.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH2:13][CH:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[CH2:18][CH2:17]3)[CH3:15])=[N:11][NH:10][C:9]2=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CI>CC#N>[CH:1]1([CH2:7][N:8]2[C:12]([CH2:13][CH:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[CH2:18][CH2:17]3)[CH3:15])=[N:11][N:10]([CH3:31])[C:9]2=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N1CCN(C(C)Cc2n[nH]c(=O)n2CC2CCCCC2)CC1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Solvent: CI
Product: COc1ccccc1N1CCN(C(C)Cc2nn(C)c(=O)n2CC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 48 %

Procedure:
To a slurry of 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-2,4-dihydro-3H-1,2,4-triazol-3-one D14 (50 mg, 0.121 mmol) and PS-BEMP (83 mg, 0.1820 mmol, 2.2 mmol/g) in MeCN (2 mL), MeI (11.5 μL, 0.182 mmol) was added and the mixture was shaken at room temperature for 64 h. The resin was filtered and the filtrate was evaporated under reduced pressure. The resulting yellow oil was purified by flash chromatography (Biotage Isolute SI, 1 g column, gradient DCM to 1% MeOH in DCM) and afforded 25 mg (48%) 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one E37 as a white solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:36](=[O:37])[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)NC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 18 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.42 g, 12.6 mmol) was added to a solution of 1-benzyl-4-piperidinamine (2.0 g, 10.5 mmol), 4-methoxyphenylacetic acid (1.83 g, 11.0 mmol), 1-hydroxybenzotriazole hydrate (1.56 g, 11.5 mmol) and triethylamine (2.70 ml, 26.2 mmol) in dichloromethane (100 ml). The reaction mixture was stirred for 18 hours after which time the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (3×), dried (MgSO4), filtered and the solvent removed under reduced pressure to afford the title compound as a white solid, 3.44 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:33]4[CH:32]=[N:31][C:30]([O:29][CH3:28])=[N:35][CH:34]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: COc1ncc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnc(OC)nc4)cc23)c1F
Reaction time: 0.27 h

Procedure:
Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (9, 10 mg, 0.022 mmol) was weighed into a 5 mL microwave vial and combined with 2-methoxypyrimidine-5-boronic acid (10, 4.4 mg, 0.028 mmol), followed by the addition of 600 μL of acetonitrile and 500 μL of 1M potassium carbonate and a spatula tip (≈1 mg) of [1,1″-bis(diphenylphosphino)-ferrocene]dichloropalladium(II). The reaction mixture was irradiated in a microwave at 160° C. for 5 minutes. The solution was neutralized with 100 μL of acetic acid and all material was transferred to a 4 mL vial and the solvents were removed under vacuum. The crude material was dissolved in 400 μL of dimetheylsulfoxide and purified by reverse phase HPLC, eluting with 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile, 20-100% acetonitrile over 16 minutes at 6 mL per minute. Appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound P-0001. MS(ESI)[M+H+]+=487.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:27]([CH3:29])[CH3:28])[CH:35]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(C)C)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.2 %

Procedure:
A mixture of 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (50 mg, 0.14 mmol), 3-isopropylphenyl boronic acid (45 mg, 0.27 mmol), copper acetate (26 mg, 0.14 mmol), triethylamine (57 μL, 0.4 mmol) and powdered 4 Å molecular sieves in DCM (1 mL) were stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (EtOAc:petroleum ether) give the title compound (32 mg, 48%).
Reaction SMILES: [Cl:1]C1C2C(=O)N[C@H]3CN(C(OC(C)(C)C)=O)C[C@@H]3C=2C=CC=1.[Cl:23][C:24]1[C:33]2[C:32](=[O:34])[NH:31][C@@H:30]3[CH2:35][N:36](C(OC(C)(C)C)=O)[CH2:37][C@H:29]3[C:28]=2[CH:27]=[CH:26][CH:25]=1>>[ClH:1].[Cl:23][C:24]1[C:33]2[C:32](=[O:34])[NH:31][C@H:30]3[CH2:35][NH:36][CH2:37][C@@H:29]3[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2NC(=O)c3c(Cl)cccc3[C@@H]2C1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2NC(=O)c3c(Cl)cccc3[C@H]2C1
Product: Cl
Product: O=C1N[C@H]2CNC[C@@H]2c2cccc(Cl)c21

Procedure:
Following the procedure described in Example 23, Part K, (3aR,9bS)-tert-butyl 6-chloro-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from Part B above, was converted into the title compound of Example 27 as an off-white solid. 1H NMR (DMSO-D6): δ 10.03 (broad s, 1H), 9.80 (broad s, 1H), 8.87 (s, 1H), 7.55-7.45 (m, 2H), 7.22 (d, 1H), 3.92-3.84 (m, 1H), 3.63-3.53 (m, 1H), 3.50-3.42 (m, 1H), 3.32-3.22 (m, 1H), 3.20-3.05 (overlapping m, 2H). LRMS (ESI): 223.07/225.05 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH:3]=[O:4].S(N)(=O)(=O)[OH:43].Cl([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:5][C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)=[CH:32][C:25]=3[S:24]4)=[CH:19][CH:20]=2)=[O:13])[CH:7]=1)([CH3:1])[C:3]([OH:43])=[O:4]
Reactant: CC(C)(C=O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C(=O)O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C

Procedure:
Alternatively final compound 2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propionic acid (I-5) is prepared by following a general procedure given in US 2005/0070549 A1. To a stirred solution of 1-[5-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-4a) (1 equivalent) in a mixture of acetic acid and water at rt is added a solution of amidosulfuric acid (1.5 equivalents) and sodium chlorite (1.5 equivalents) in water, and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is neutralized with 30% aq sodium hydroxide and partitioned between water and either dichloromethane or a mixture of isopropanol and dichloromethane. The separated aqueous layer is further extracted with dichloromethane or a mixture of isopropanol and dichloromethane, and the combined organic layers are washed with water or brine dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propionic acid (I-5).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: O=C1NCCO1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(N3CCOC3=O)nc2)CC1
Yield: 12.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 31 and using (6-bromopyridin-3-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (2 g) described in Preparation Example 23 and oxazolidin-2-one (435 mg), the title compound (260 mg) was obtained.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][CH:10]([C:16]([CH3:18])=O)[C:11](OCC)=[O:12].S(=O)(=O)(O)O>>[CH3:9][C:10]1[C:11](=[O:12])[O:2][C:1]2[C:8]([C:16]=1[CH3:18])=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=2
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: O=S(=O)(O)O
Product: Cc1c(C)c2ccc(O)cc2oc1=O
Yield: 82.1 %

Procedure:
Resorcinol (5.5 g) and 7.2 g of ethyl 2-methylacetoacetate were stirred at 10° C. for 3 hours in the presence of a catalytic amount concentrated sulfuric acid to give 7.8 g (yield 83%) of 3,4-dimethyl-7-hydroxycoumarin. The product was hydrogenated and dehydrated as in Referential Example 16 to give 5.7 g (78%) of the desired product as a pale brown liquid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[CH2:31]([O:33][CH:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)[CH3:32]>>[CH2:31]([O:33][CH:34]1[CH2:39][CH2:38][CH:37]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:35]1)[CH3:32]
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CCOC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC1CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-ethoxy-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:13](=[O:20])(=[O:19])[NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:7]2[OH:12].N1C=CC=CC=1.[O:27]1[CH2:32][CH2:31][N:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:29][CH2:28]1.Cl>O>[C:15]([NH:14][S:13]([C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][S:33]([N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)(=[O:35])=[O:34])[C:7]=1[OH:12])(=[O:20])=[O:19])([CH3:17])([CH3:16])[CH3:18]
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(N)cccc2c1O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(NS(=O)(=O)N3CCOCC3)cccc2c1O
Temperature: 0 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
To a mixture of 9 g. of 5-amino-2-tert-butylsulfamoyl-1-naphthol with 90 ml. of pyridine were added portionwise under ice-cooling and stirring 11 g. of morpholinosulfonyl chloride and stirring was continued at room temperature for 20 hours. Thereafter, 10 ml. of water were added and stirring was carried out for further 1 hour. Into a mixture of 115 ml. of conc. hydrochloric acid with 400 ml. of ice-water was poured the above reaction mixture to separate a solid precipitate, which was then collected on a filter funnel and washed with water. The product was dissolved in an alkaline solution of 6 g. of sodium hydroxide in 150 ml. of water, insolubles were filtered off, the filtrate was poured into a mixture of 15 ml. of conc. hydrochloric acid with 150 ml. of ice-water to separate a solid precipitate. The precipitate was collected on a filter funnel, washed well with water and then dried to afford 9.6 g. of the desired product in a yield of 72%. mp. 105°-110° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:32]=[N:33][C:34]([Cl:37])=[CH:35][CH:36]=3)=[O:29])=[C:23]([Br:38])[CH:22]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C>[Br:38][C:23]1[CH:22]=[C:21]([CH:17]2[O:18][CH2:19][CH2:20][NH:15][CH2:16]2)[CH:26]=[CH:25][C:24]=1[NH:27][C:28]([NH:30][C:31]1[CH:32]=[N:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)Nc3ccc(Cl)nc3)c(Br)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc(Cl)nc1)Nc1ccc(C2CNCCO2)cc1Br
Temperature: 80 °C
Reaction time: 5 h
Yield: 67.6 %

Procedure:
To a stirred solution of trifluoroacetic acid (90 μl) in water (6 ml) was added a solution of (RS)-2-{3-bromo-4-[3-(6-chloro-pyridin-3-yl)-ureido]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (46 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 5 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford (RS)-1-(2-bromo-4-(morpholin-2-yl)phenyl)-3-(6-chloropyridin-3-yl)urea (25 mg, 68%) as an off-white solid. MS (ISP): 415.0 ([{37Cl81Br}M+H]+), 413.0 ([{37Cl79Br or 35Cl81Br}M+H]+), 411.0 ([{35Cl79Br}M+H]+).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13])(=[O:5])=[O:4])[CH3:2].[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[Br:15][CH2:13][C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[O:14]
Reactant: [Br-]
Reactant: CCS(=O)(=O)c1ccccc1C(C)=O
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 164 %

Procedure:
A mixture of 1.0 g of 2′-ethylsulfonylacetophenone, 1.86 g of phenyltrimethylammonium tribromide and 10 ml of THF was stirred at room temperature for 3 hours. A 10% aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to obtain 1.37 g of 2-bromo-2′-ethylsulfonylacetophenone.